Increased cell-to-cell variation in gene expression in ageing mouse heart

Bahar, Rumana; Hartmann, Claudia; Rodriguez, Karl A.; Denny, Ashley D.; Busuttil, Rita A.; Dollé, Martijn E.T.; Calder, R. Brent; Chisholm, Gary B.; Pollock, Bradley H; Klein, Christoph A.; Vijg, Jan

doi:10.1038/nature04844

Cited by 535 publications

(460 citation statements)

References 18 publications

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“…Telomere shortening is paralleled by activation of a DDR (4,5). Recent studies show that oxidative stress as well as mutations in DNA repair pathways provoke epigenetic alterations and transcriptional changes paralleling those observed in aged animals (13,22,32). Here we show that accumulation of dysfunctional telomeres, associated with broad alterations of the mouse transcriptome and impaired maintenance of epigenetic silencing during X inactivation.…”

Section: Discussionmentioning

confidence: 65%

Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations

Schoeftner

Blanco

Silanes

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Telomeres are heterochromatic structures at chromosome ends essential for chromosomal stability. Telomere shortening and the accumulation of dysfunctional telomeres are associated with organismal aging. Using telomerase-deficient TRF2-overexpressing mice (K5TRF2/Terc ؊/؊ ) as a model for accelerated aging, we show that telomere shortening is paralleled by a gradual deregulation of the mammalian transcriptome leading to cumulative changes in a defined set of genes, including up-regulation of the mTOR and Akt survival pathways and down-regulation of cell cycle and DNA repair pathways. Increased DNA damage from dysfunctional telomeres leads to reduced deposition of H3K27me3 onto the inactive X chromosome (Xi), impaired association of the Xi with telomeric transcript accumulations (Tacs), and reactivation of an X chromosome-linked K5TRF2 transgene that is subjected to X-chromosome inactivation in female mice with sufficiently long telomeres. Exogenously induced DNA damage also disrupts Xi-Tacs, suggesting DNA damage at the origin of these alterations. Collectively, these findings suggest that critically short telomeres activate a persistent DNA damage response that alters gene expression programs in a nonstochastic manner toward cell cycle arrest and activation of survival pathways, as well as impacts the maintenance of epigenetic memory and nuclear organization, thereby contributing to organismal aging.aging ͉ chromosome X inactivation ͉ DNA damage ͉ epigenetics ͉ telomeres D ysfunctional, critically short telomeres elicit a DNA damage response (DDR) that triggers senescence or apoptosis in mammalian cells, two processes that are associated with organismal aging (1-9). Mice with a targeted deletion of the RNA component of telomerase (Terc Ϫ/Ϫ ) display accelerated telomere shortening, premature loss of tissue renewal, and decreased longevity (3,(7)(8)(9). DNA damage signals originating from critically short telomeres in these mice is in line with current models proposing a causative role for DNA damage in organismal aging (10-13). Interestingly, epigenetic alterations at heterochromatic regions are proposed to lead to changes in gene expression associated with aging (14-16). In S. cerevisiae, induction of DNA double-strand breaks (DSBs) or cellular stress causes a dramatic redistribution of telomeric silent information regulator (Sir) proteins and yKU proteins (17-19), thus linking changes in telomere chromatin to global epigenetic alterations. Sir complex relocalization is known to alter the expression of stress response genes, survival factors, and ribosomal biogenesis (20,21). In functional analogy to yeast, mammalian SIRT1 is redistributed upon induction of DNA damage, causing broad alterations in global gene expression (22). Collectively, these findings suggest that agingrelated DNA damage drives gene expression alterations that could promote the development of aging pathologies.An important question to determine is how the various types of DNA damage impact gene expression changes associated with organismal a...

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Section: Discussionmentioning

confidence: 65%

Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations

Schoeftner

Blanco

Silanes

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Importantly, linking back to the previous discussion of PEV, some of these changes appear to have a stochastic component. For example, aging is associated with increased variability in gene expression in cardiomyocytes [104]. Aging hematopoietic stem cells also exhibit changes in gene expression.…”

Section: The Consequences Of Age-associated Epigenetic Changesmentioning

confidence: 99%

“…However, if CpG hypermethylation is a frequent age-associated, tissue-wide, pre-neoplastic event, it might be possible to extend this technology to cancer risk assessment, based upon age-associated hypermethylation in preneoplastic tissue. Likewise, it might also be possible to use age-associated epigenetic changes in cardiac or immune cells for risk assessment or early detection of cardiovascular disease or declining immune function [104][105][106].…”

Section: Summary Outstanding Questions and Therapeutic Implicationsmentioning

confidence: 99%

Aging by epigenetics—A consequence of chromatin damage?

Sedivy

Gowrishankar

Adams

2008

Experimental Cell Research

136

101

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Chromatin structure is not fixed. Instead, chromatin is dynamic and is subject to extensive developmental and age-associated remodeling. In some cases, this remodeling appears to counter the aging and age-associated diseases, such as cancer, and extend organismal lifespan. However, stochastic non-deterministic changes in chromatin structure might, over time, also contribute to the break down of nuclear, cell and tissue function, and consequently aging and age-associated diseases.

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“…As phenotypic heterogeneity in cell populations typifies diverse (patho-) physiological conditions and processes (61)(62)(63) it may be informative to distinguish specific cellular stereotypes under varying conditions. Similarly, automatic identification of aberrant or novel phenotypes may prove useful in functional screening (64,65).…”

Section: Discussionmentioning

confidence: 99%

High content image cytometry in the context of subnuclear organization

et al. 2009

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The organization of proteins in space and time is essential to their function. To accurately quantify subcellular protein characteristics in a population of cells with regard for the stochasticity of events in a natural context, there is a fast-growing need for image-based cytometry. Simultaneously, the massive amount of data that is generated by image-cytometric analyses, calls for tools that enable pattern recognition and automated classification. In this article, we present a general approach for multivariate phenotypic profiling of individual cell nuclei and quantification of subnuclear spots using automated fluorescence mosaic microscopy, optimized image processing tools, and supervised classification. We demonstrate the efficiency of our analysis by determination of differential DNA damage repair patterns in response to genotoxic stress and radiation, and we show the potential of data mining in pinpointing specific phenotypes after transient transfection. The presented approach allowed for systematic analysis of subnuclear features in large image data sets and accurate classification of phenotypes at the level of the single cell. Consequently, this type of nuclear fingerprinting shows potential for high-throughput applications, such as functional protein assays or drug compound screening. ' 2009 International Society for Advancement of Cytometry

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Increased cell-to-cell variation in gene expression in ageing mouse heart

Cited by 535 publications

References 18 publications

Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations

Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations

Aging by epigenetics—A consequence of chromatin damage?

High content image cytometry in the context of subnuclear organization

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